Prevention of Calcium Ionophore-Induced Release of Histamine in Rat Mast Cells by Disodium Cromoglycate

Abstract

Our results confirm the observations of Foreman et al. (10) that calcium-specific ionophores can initiate histamine release. In an accompanying communication (17) the production of a substance resembling SRS-A under the influence of A23, 187 is also reported. In this study we addressed ourselves to the question: “Can these ionophores be used as a tool to study DSCG's mechanism of inhibition of secretory histamine release?” DSCG does not chelate divalent cations very well (2, 12), but this conclusion is based on measurements of Ca in the free medium. Under similar conditions in which the EDTA shows significant evidence of complex formation with divalent cations the pH titration curve of DSCG is unaffected. The calcium involved in histamine release may be cell bound in a specific spatial arrangement that lends itself to “tying” up by DSCG at the cell surface. Thus, it is possible that one of the ways that DSCG inhibits is by preventing the increased uptake of calcium by cells under the influence of histamine release initiators such as compound 48/80 or antigen-antibody reactions, and thereby inhibiting mediator release. Physicochemical studies on binding to cell-bound ions by DSCG will be required to answer this point. DSCG can exist in a water lattice form that may have a specific binding capacity when divalent cations like calcium are present (18). It may thus exert its effect by existing in juxtaposition to the cell surface and binding ions, rather than actually binding to the mast cells. This juxtaposition could result in decreased calcium movement and diminished release of histamine. These studies do not answer the questions of peculiar self-inhibition effects seen with DSCG, nor do they explain the biphasic nature of the drug's dose response in most in vitro cells systems. They are consistent with DSCG being involved in Ca economy of the cells, but it may also inhibit some unidentified enzyme needed for release. Self-inhibition effects of DSCG in ionophore-induced release are being studied as well as desensitization as a consequence of calcium deprivation to the cell and will be reported at a later date.